In orthopedic and dental surgical applications there is a great need for biocompatible and bioresorbable implant material which can be conveniently and effectively used as a bone substitute. This includes bone lost due to periodontal disease, ridge augmentation, sinus elevation, bone defects or cavities due to trauma, disease or surgery and spinal fusions. Following implantation the bone substitute is ideally resorbed in a time frame which is consistent with its replacement by new vital bone.
The bone graft material of preferred choice is autograft, i.e. the patient's own bone, since this is totally biocompatible, is not subject to an immune response or disease transmission and has good osteogenic capacity. However, its source is limited, it requires a second surgical procedure for harvest and there are often donor site morbidity problems.
Allograft bone is usually considered an acceptable alternative since it is more readily available and has a reasonable level of efficacy. However, it has the potential for disease transmission and since it is ‘foreign’ tissue there is the potential for immunological reactions. In addition, it is a material variable in its properties, due to donor source (often elderly people with osteoporotic bones) and processing variability. This makes prediction of clinical outcome difficult when allograft is used. Delayed healing is a frequent complication.
Calcium sulphate and calcium phosphate bone cements consist of a powder and an aqueous liquid component. Mixing of these components gives a material having a paste consistency and results in a chemical hydration reaction leading to stiffening and setting of the mixture as the reaction proceeds to completion. It is increasingly required in many surgical procedures to add therapeutic agents to the bone cement to deliver the agent to the surgical site. This is often the case in cases of bone infection where the presence of locally delivered antibiotic or antifungal agents can have significant advantages compared to the traditional oral or parenteral delivery route. These therapeutically active materials are added to the cement when the powder and liquid components are mixed together. As such they then become homogeneously incorporated and uniformly distributed throughout the set/cured cement.
Multi-drug resistant (MDR) bacterial strains are now widespread in all hospitals. Increasingly high doses of antibiotics are needed in order to provide concentration levels which exceed the minimum inhibitory concentration (MIC) required to effectively kill all bacteria. If administered intravenously this increases the potential for systemic toxicity effects, in addition to further increasing the potential for bacterial resistance. It is being increasingly recognised that the delivery of the antibiotic directly to the contaminated site is the best way to exceed the MIC while limiting systemic toxicity effects. Poly-methyl methacrylate (PMMA) cement is often used as a carrier for antibiotic delivery. It does have, however, a number of disadvantages. It cures at a relatively high temperature, over 80° C. for sections thicker than a few millimeters, and many antibiotics are not thermally stable at these temperatures. It is a non-resorbing material and as such the beads must be removed in a second surgical procedure following eradication of the infection. Because of the non-resorbing nature of the PMMA much of the antibiotic that is mixed with the material is ‘locked in’ and only a small proportion is eluted. For these reasons, calcium sulphate and calcium phosphate bone cements are being used as carriers for the local delivery of antibiotics and other therapeutically active materials.
Identification of the type of bacterial contamination is essential. The surgeon will choose the appropriate antibiotic or antifungal for the type of pathogen involved. It is often advantageous to use a combination of two or more antibiotics to ensure satisfactory killing efficiency. The antibiotics are thoroughly mixed with the bone cement at the time of surgery. The mixture can be cast into a suitable mould where it is allowed to cure or set or simply administered to the surgical site and allowed to cure in situ. Following hardening the pellets can be removed from the mould by flexing the mould. To allow this flexing the mould is made from a flexible polymer such as a silicone resin.
Many therapeutic agents including antibiotics, antifungals, antivirals, NSAIDs and proteins or proteinacious material can have a significant effect on the setting time of bioactive (calcium sulphate and calcium phosphate) bone cements. Some materials will retard the setting process while others will inhibit setting completely. When mixed at the time of surgery it is important for these mixtures to set in a time frame consistent with the timing of the procedure, typically within the range of a few up to about 20 minutes. This will enable the surgical team to prepare the bone cement pellets, allowing them to harden, and implant them at the time of surgery.
There is thus a requirement for a method to ensure that therapeutic agents which retard or inhibit setting can be added to a bioactive bone cement mixture which subsequently sets within this time frame.